Abstract: Identifying Novel Biological Pathways for Gout using DNA Methylation and Genetics Gout is the most common form of inflammatory arthritis and affects ~8 million U.S. adults. Patients with gout experience intensely painful flares associated with impaired quality of life and high levels of healthcare utilization. With increasing prevalence of risk factors for gout, such as older age, obesity, hypertension, chronic kidney disease, and hyperuricemia, the incidence and prevalence of gout and its public health importance are all rising. However, gout is understudied compared to other rheumatologic conditions. Discovery of novel risk factors for gout can enhance our understanding of the disease susceptibility and identify targets for prevention and treatment. Gout attacks are inflammatory responses to the deposition of monosodium urate crystals in articular tissues causing rapidly intensifying painful and swollen joint(s). However, most individuals with hyperuricemia do not development gout. Our understanding of individual variation in susceptibility to acute gout is limited. The immune response is known to be involved in gout flares, including activation of the inflammasome. Emerging evidence supports links between inflammation and DNA methylation levels. However, factors influencing DNA methylation levels and their consequences for chronic disease remain to be elucidated. The examination of DNA methylation in whole blood has the potential to uncover epigenetic risk factor for gout. DNA methylation levels may also be intermediaries of environmental and genetic risk factors for gout and thus could yield insight into the biological pathways mediating gout flares or may serve as biomarkers for exposure to environmental risk factors. The overarching goal of this study is to uncover epigenetic factors that can illuminate the biological pathways underlying gout susceptibility and/or serve as biomarkers for the prediction of gout. Our aims are : (1) to identify DNA methylation sites associated with incident gout; (2) to identify DNA methylation sites associated with serum urate levels followed by (i) evaluating the potential causal relation between associated DNA methylation sites and serum urate using a Mendelian randomization approach, and (ii) an in-depth investigation of the urate-associated sites that have been linked to blood pressure; (3) to develop and validate risk prediction models for gout incorporating data from: (i) clinical, (ii) genetic and (iii) epigenetic risk factors, and examine how factors beyond serum urate levels add to risk prediction across sexes and over intermediate and longer time periods. This proposed study will accelerate research on gout prevention and treatment by identifying potentially reversible epigenetic factors related to incident gout and urate levels. The gout risk prediction models will lay the foundation for risk stratification strategy for future intervention trials for gout treatment and management, particularly among high- risk patients in whom treatment to serum urate target is particularly important.